The theme of our Program is the development of a vaccine against SIV, using SIV as a model for HIV. The development of an HIV vaccine is hampered by the lack of knowledge of mechanisms of protection against this type of virus and the molecular target of a protective response. This program addresses the parameters of efficient vaccination of macaques with SIV antigens and contains the following topics: - development of a reliable challenge system in macaques, - attempts to vaccinate macaques with inactivated SIV, - development of recombinant SIV antigens from SIV molecular clone BK28 production of antigens in different vehicles and adjuvant formulations (Iscoms, Colloidomes, Liposomes); administration of antigen combinations to monkeys (Emphasizing denatured env gp160, CD4-env complexes and env conserved sequences) - analysis of protection to the challenge with BK28 variant, - cloning and analysis of a pathogenic SIV variant, - if protection to homologous challenge is observed, challenge with the more pathogenic variant or a pathogenic pool of virus will be performed, - therapeutic vaccination, - analysis of the capacity of env-based vaccines to alter CD4 lymphocyte and monocyte function in vitro. - definition of the rate of SIV genome evolution in vivo and identification of pathogenic determinants of SIV by in vivo testing of chimeras between pathogenic and non pathogenic viral clones. The Principal Investigator, Dr. Burny (University of Brussels) will produce SIV recombinant antigens (gag, pol, env, nef) in three different adjuvant formulations (iscoms, colloidomes, liposomes). Dr. Burny's group will study the role of syncytia induction in verbal pathogenesis and capacity of escape from the host immune response (with Dr. Ruysschaert). Dr. Mullins will attempt to isolate a molecularly cloned pathogenic strain of SIV. He will identify the pathogenic determinants of SIV and follow the rate of SIV genome evolution in vivo in collaboration with Drs. Fultz and Hoover. Drs. Fultz and Hoover will assess the potential of the various vaccine preparations as prophylactic and therapeutic treatments. In addition to providing the immunological reagents and test required for antigen identification and characterization, Dr. Bruck will prepare CD4-gp160 complexes, fragments of gp160 and pseudovirions of SIV as potential vaccines. She will perform serological tests and analyze the immune response of vaccinated macaques in collaboration with Drs. Fultz and Hoover. Dr. Kornfeld will study in vitro the response of CD4 cells to candidate SIV (and HIV) vaccines, mostly those preparations containing env determinants. If a successful and non-toxic candidate is identified in the macaque system, the corresponding HIV recombinant-proteins (most of them already available at Smith Kline-RIT) will be proposed for application in humans.